Methamphetamine (METH) and cocaine (C0C) differ in their neurotoxic potential despite the fact that they both increase the release of monoamine neurotransmitters. These monoamines act on neurons in the basal ganglia to alter the function of the opioid peptides, dynorphin A (DYN) and met-enkephalin (M-ENK), which have been implicated in the toxic effects of METH. High, equimolar doses of METH and COC differentially increase the mRNA expression of pre-pro-dynorphin in distinct striatal compartments. These doses of METH and COC also have different effects on striatal concentrations of DYN peptide. Finally, non- toxic doses of METH decrease M-ENK concentrations in striatum, whereas neurotoxic doses increase it. Thus, METH and COC, especially at high doses, differentially regulate opioid peptide systems in striatal efferent neurons. These findings lead to the hypothesis that differences in the effects of METH and COC on opioid peptide systems in striatal efferent neurons contribute to the differential long-term consequences of psychostimulant exposure. This hypothesis will be tested by completing the following specific aims. 1) We will determine the effects of opioid receptor agonists and antagonists on METH induced toxicity to central monoamine systems and correlate the patterns of opioid peptide release induced by various doses of METH, as well as COC, with the patterns of neurotoxicity observed. 2) We will determine the mechanisms underlying the differential effects of METH and COC on the opioid peptides in the dorsal striatum and nucleus accumbens. This will be accomplished by comparing peptide responses to doses of METH and COC that produce equivalent increases in extracellular monoamines. Furthermore, because different degrees of dopamine release are likely to differentially, affect receptors and signaling pathway, we will determine the differential involvement of dopamine, serotonin, and acetylcholine receptors and second -messenger systems in the effects of METH and COC. 3) Finally, as a point of integration with Projects 2 and 4, we will determine the long-term consequences of the differential neurotoxicity to monoamine systems and seizure activity produced by METH and COC on the basal activity of the opioid peptide systems and their responsiveness to acute psychostimulant challenge in the dorsal and ventral striatum. These data will provide us with a comprehensive understanding of the role of DYN and M-ENK in these peptides, and the long-term consequences of METH- and COC-induced toxic effects on these systems. Such insight will provide a foundation for the development of selective therapeutic agents to address the short- and long-term consequences of these drugs of abuse.